DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional application 63/140,705 (filed 01/22/2021).
Election/Restrictions
Applicant’s election without traverse Group I, corresponding to claims 1-20, in the reply filed 02 July 2026 is acknowledged. Claims 21-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02 July 2026.
Claim Objections
Claim 1 is objected to because of the following informalities: “(vii)” should read “(vi)”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “at least one helper polypeptide, in medium” in line 8. It is unclear if Applicant requires the transfection to occur in medium or if only the “at least one helper polypeptide” is required to be in medium. The dependent claims do not add additional clarity and, therefore, are also indefinite.
For the purposes of compact prosecution and applying prior art, claim 1 is being interpreted as transfecting the host cells in medium.
The term “substantially” in claim 5 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The timing of the addition of the microtubule destabilizing agent is rendered indefinite by the use of the term “substantially”.
The term “about” in claims 7-8 and 11 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The timing of the addition of the microtubule destabilizing agent and rAAV titer are rendered indefinite by the use of the term “about”.
The term “higher” in claims 9 and 11 is a relative term which renders the claim indefinite. The term “higher” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised on the scope of the invention. The rAAV titer is rendered indefinite by the use of the term “higher”. The dependent claim 10 does provide additional clarity and therefore, is not also indefinite.
For the purposes of compact prosecution and applying prior art, the term “higher” in claims 9 and 11 will be defined by the definition provided in claim 10.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation
of the claims is different than that posited by the Examiner, additional rejection and art
may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-12, 14-15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Li, et al. (US 20050112765 A1, US-IDS, filed, 07/02/2026, hereinafter “Li”) and further in view of Arulanandam, et al. (Nat Commun. 2015 Mar 30;6:6410., hereinafter “Arulanandam”) and evidenced by Wang, et al. (BMC Pharmacol Toxicol. 2019 Nov 13;20(1):66., hereinafter “Wang”) and Malm, et al. (Sci Rep. 2020 Nov 4;10(1):18996., hereinafter “Malm”).
Regarding claims 1 and 12, Li teaches a method of producing recombinant adeno-associated virus (rAAV) particles (claim 70) comprising providing/transfecting (¶0005) host cells with one or more vectors encoding a recombinant adenovirus encoding (a) one or more Rep and Cap polypeptides, (b) a gene of interest flanked by inverted terminal repeats (ITR), and (c) a helper virus, culturing the host cells to produce rAAV (Claim 70).
Li does not teach adding at least one microtubule destabilizing agent to the medium. However, Arulanandam teaches that microtubule destabilizing agents promote virus spread in cancer cell lines (pg. 2 column 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Li for a method of producing rAAV with the teachings of Arulanandam for a microtubule destabilizing agent. Arulanandam provides motivation by teaching that microtubule destabilizing agents promote virus spread in cancer cells lines (pg. 2 column 2, Fig 1c, e and Supp. Fig, 1 e, f). It would have been obvious to one of ordinary skill in the art that adding a microtubule destabilizing agent to Li’s method would further increase the yield of AAV vector from cells due to the increased viral spread. One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Li and Arulanandam because they both teach viral infection of cell cultures.
Regarding claims 2-3, Arulanandam teaches that the microtubule destabilizing agent is colchicine (pg. 2 column 2), a G2/M inhibitor as evidenced by Wang (Abstract).
Regarding claims 4-7, Arulanandam teaches pretreating the cells with colchicine 2-4 hours before infection (pg. 11, column 2).
Regarding claims 5-6 and 8, Li and Arulanandam do not teach adding the microtubule destabilizing agent simultaneously with the one or more vectors or after transfection. However, routine optimization of the optimal time of addition for the microtubule destabilizing agent taught by Arulanandam would have led to the claimed addition times of simultaneously or after transfection because colchicine is a G2/M inhibitor which arrests cell proliferation (Wang, abstract). The person of ordinary skill in the art would have optimized this parameter to determine the best time to arrest cell proliferation that would lead to the highest rAAV yield. Routine optimization and testing would lead to an ideal time period to yield the highest rAAV titer. The person of ordinary skill in the art would have found it obvious to optimize the time the microtubule destabilizing agent is added to cells because colchicine arrests cell proliferation and changing when the agent is added would change when cell proliferation was arrested which would affect rAAV yield.
Regarding claims 9-11, Arulanandam teaches that microtubule destabilizing agents (MDAs) promote viral spread (pg. 2 column 2). Arulanandam and Li do not teach that adding MDAs to cells increases rAAV titer 1-6-fold higher than without MDAs. However, absence evidence to the contrary, the method taught by Li and Arulanandam would lead to 1-6-fold higher titers of rAAVs when compared to methods without MDAs. The titer levels are not an additional step to be performed, but, rather, the inherent result of practicing the method taught by Li and Arulanandam. See MPEP §2112.
Regarding claim 14, Li teaches that the helper virus comprises a gene or polypeptide that comprises viral helper functions which are provided by E1a, E1b, E2a, E4ORF6, and VA RNA (¶0195-0197).
Regarding claims 15 and 17-18, Li teaches that the host cells are HEK-293 cells (Claim 73). As evidenced by Malm, HEK293 cells are adherent cells (pg. 2, ¶3).
Regarding claim 19, teaches that the HEK-293 cells express E1 (¶0217).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Claims 13 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Li and Arulanandam as applied to claims 1-12, 14-15, and 17-19 above, and further in view of Hörer, et al. (WO 2020208379 A1, FOR-IDS, filed 07/02/2026, hereinafter “Horer”).
As discussed above, claims 1-12, 14-15, and 17-19 were rendered prima facie obvious over Li and Arulanandam.
Regarding claim 13, Li and Arulanandam do not teach a two-plasmid system for producing rAAVs. However, Horer teaches a two-plasmid system comprising a helper plasmid that comprises at least one rep gene encoding a Rep polypeptide (claim 1) and a vector plasmid comprising one cap gene encoding a Cap polypeptide and a gene of interest (claim 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Li and Arulanandam for a method of producing rAAV with adding a microtubule destabilizing agent with the teachings of Horer for a two-plasmid system. Horer provides motivation by teaching that multi-plasmid systems are costly and that the more plasmids used to lower the likelihood all plasmids would enter the same cell to produce rAAV (pg. 1 lines 27-33). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Li, Arulanandam, and Horer because they all teach infection of cell cultures.
Regarding claim 20, Horer teaches transfecting HEK293T cells with helper and vector plasmids in the presence of PEIpro™, a polyethyleneimine transfection reagent (pg. 94, line 31).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Li and Arulanandam as applied to claims 1-12, 14-15, and 17-19 above, and further in view of Blessing, et al. (Mol Ther Methods Clin Dev. 2018 Nov 22;13:14-26., hereinafter “Blessing”).
As discussed above, claims 1-12, 14-15, and 17-19 were rendered prima facie obvious over Li and Arulanandam.
Regarding claim 16, Li and Arulanandam do not teach that the host cells are ins suspension. However, Blessing teaches a scalable process for rAAV production, using orbitally shaken bioreactors and a suspension-adapted cell line, HEKExpress (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have substituted the adherent cells taught by Li for the cells in suspension taught by Blessing. Blessing provides motivation by teaching that rAAVs derived from suspension HEKExpress cells have a higher potency that those that were produced from adherent cells (Abstract). One of skill in the art would have a reasonable expectation of success in substituting the adherent cells taught by Li for the suspension cells taught by Blessing because they are both HEK cell lines used in the production of rAAVs.
Conclusion
NO CLAIMS ARE ALLOWED
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/CASSANDRA SENN GRIZER/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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